Office of Generic Drugs (OGD) Director’s Update · PDF fileOffice of Generic Drugs (OGD) Director’s Update ... February 23, 2016 . 2 Disclaimer • This presentation reflects

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Office of Generic Drugs (OGD) Director’s Update

Kathleen Uhl, MD

Director, Office of Generic Drug CDER/FDA

GPhA Annual Meeting

February 23, 2016

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Disclaimer

• This presentation reflects the views of the speaker and do not reflect official FDA, HHS, or other government opinion or policy.

• I have nothing to disclose.

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OUTLINE

1. GDUFA update 2. Output & Productivity 3. Quality of ANDA Submissions 4. Update on Pre-Year 3 cohort 5. Opportunities for Improvement & Challenges

Common Problems seen in ANDAs Ways for Industry to “Control your Destiny”

GDUFA IMPLEMENTATION • Agency is meeting ALL of its obligations

under GDUFA commitment letter • We are going above and beyond the

commitments • Building a modern, 21st Century generic

drug program • Resulting in significant and sustained

increase in communications, actions & approvals 4

GDUFA IMPLEMENTATION • Productivity up: actions and APs/TAs • Communications up: hundreds/month • Pre Year 3 ANDAs:

– TADs issued and communicated to industry – Formula for review timeframes – Workload knowledge

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First QTR FY2016 (October, November, December 2015)

• Approvals - 190 • Tentative Approval (TA) - 48 • Complete Response (CR) – 310 • December 2016 – highest number of

approvals/TA in one month EVER - 99

• In CY2015 – broke 700 AP + TA HIGHEST NUMBER EVER

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OUTLINE



GDUFA MAJOR PROGRAM GOALS

(5 year plan) 1. Metrics

– Applications – GDUFA Backlog – cGMP Inspections

2. Efficiency enhancements 3. Regulatory science

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TRANSPARENCY (facility identification & communication) SAFETY

(high quality standards)

ACCESS (predictability & timeliness in review process)

GDUFA IMPLEMENTATION Build the Machine

• Deep foundational restructuring • Build infrastructure • Improve business processes • Hire and train new staff • New IT platform • Improve communications

• All to prepare for Year 3 Goal Dates AND to enable

us to hit goal dates

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GDUFA Hiring Progress

IT IMPROVEMENTS • Improved communication and increased

productivity are the direct result of our improved IT system for the generic drug program

• Provides workload management & review management tools

• Enables prioritization process for 1st generics, PIVs, exclusivity type issues

• OVER 130,000 assignments in new Platform 11

CDER Informatics “Platform”

New Capabilities & Functions Benefits to FDA & Industry

• Ensures synchronization of data across

Integrated Data

•

•

CDER to assure high data quality Provides a single source of truth for application and submission data Supports transition to more electronic

• Supports faster review times (e.g. 25% improvement in FY15

Management submissions approvals and tentative approvals year over year)

• One-stop-shop to manage, execute, track

and report on work commitments • Makes it easier to collaborate • Promotes transparency across CDER into and communicate with Industry

Integrated Workflow

Management •

all application projects and tasks Enables collaboration and communication on reviews and assignments across cross-functional teams

• Improves review consistency by making it easier to study precedent applications

• Makes ANDA review times and target completion dates more

• Faster, more powerful search across all application types and documents

• Dashboards and metrics to monitor predictable Analytics, progress and risk

Search and • Increased analytic capabilities to support Reporting data driven decision making

1,623

Submission Linkages Created

New Originals Created

(ANDA-NDA-BLA-IND)

1,086 39,521 A p p l i c a t i o n s F a c i l i t i e s

Products Created 2,995

P r o d u c t s

23,724 Ingredients linked

25,877 Business operations

created

13,206 Business Operations

Updated

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13,067 MDM IDs Updated

DUNS Updated FEIs Updated

1,634/ Issues Resolved in Panorama 5,436/ Unique Panorama

Projects Assigned

D a t a Q u a l i t y

12,688/ Tasks Completed in Panorama

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SCOPE of IT IMPROVEMENTS Improving Data Quality

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Goals FY2015 FY2016 FY2017

Original ANDA 60% in 15 months 75% in 15 months 90% in 10 months

Tier 1 first major amendment 60% in 10 months 75% in 10 months 90% in 10 months

Tier 1 minor amendments (1st - 3rd) 60% in 3 months* 75% in 3 months* 90% in 3 months*

Tier 1 minor amendments (4th - 5th) 60% in 6 months* 75% in 6 months* 90% in 6 months*

Tier 2 amendment 60% in 12 months 75% in 12 months 90% in 12 months

Prior approval supplements 60% in 6 months* 75% in 6 months* 90% in 6 months*

ANDA teleconference requests Close-out 200 Close-out 250 Close-out 300

Controlled correspondences 60% in four months* 70% in two months* 90% in two months*

ANDA, amendment and PAS in backlog on Oct 1, 2012

Chart 4. Major GDUFA Performance Goals**

*10 months if inspection required**Performance goals in the chart means FDA should take an action on a certain percent of applications, etc. w ithin the timeframes listed; it does not mean FDA should approve applications, etc. w ithin such timeframes.

Act on 90% by end of FY 2017

GDUFA GOAL DATES Powerful tool to improve the timeliness and predictability of review

Filing Review (OGD)

IR #1

Response Received

and Reviewed

Complete Inspection

Wrap up and Final Review

0 – 60d 4mo – 6.5mo

Within 7.0mo

Within 9.0mo

Kick-Off Meeting

Within 90d

Assessment #1 and

Cumulative IR #1

Within 120d

IR #2

Response Received

and Reviewed

6.5mo – 8.5mo

Review Team

Assignment

Within 70d

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OGD & OPQ believe, in working with Industry, by Year 5 the 1st cycle approvability rate for ANDAs can be improved.

This goal is achievable provided the ANDA submissions we receive are of high quality and complete upon first submission.

Proposed example of Year 5 timeline:

PREDICTABILITY for INDUSTRY

GDUFA

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TRANSFORM THE PROGRAM and

PERFORM WHILE TRANSFORM

We built the machine… NOW we are cranking it up!

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OUTLINE



OUTPUT & PRODUCTIVITY INCOMING from INDUSTRY

OUTPUT from FDA • GDUFA Backlog • ANDAs • PASs • Filing • Communication • Controlled

Correspondence • Guidance

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PROJECTED vs ACTUAL ANDA RECEIPTS

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ANDA Receipts

*Numbers are based on current data and will be further scrubbed for formal reporting purposes

ACTUAL ANDA RECEIPTS

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CONTROLLED CORRESPONDENCE RECEIPTS

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FY2012 FY2013 FY2014 FY2015*

ANDA approvals 517 440 409 490

Tentative Approval (TA)

102 95 91 120

PAS approvals

275 535 659 624

Complete Response (CR)

84 1251 1254 1007

TOTAL **

978 2226 2413 2241

DMF Completeness Assessment (CA)

0 1699 1706 901

* Numbers are based on current data and will be further scrubbed for formal reporting purposes ** FDA will aspire to the extent possible to maintain levels of productivity at least similar to pre-GDUFA levels, while hiring and training incremental staff necessary to achieve the program performance goals, building necessary systems and implementing outlined program changes in years 1 and 2 of the program (GDUFA Commitment Letter, page 3)

OVERALL ACTIONS PRE-GDUFA GDUFA

ANDA Approvals PRODUCTIVITY

23 ** FDA will aspire to the extent possible to maintain levels of productivity at least similar to pre-GDUFA levels, while hiring and training incremental staff necessary to achieve the program performance goals, building necessary systems and implementing outlined program changes in years 1 and 2 of the program (GDUFA Commitment Letter, page 3) *Numbers are based on current data and will be further scrubbed for formal reporting purposes

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APPROVALS AND TENTATIVE APPROVALS FY2014, FY2015 & 1st QTR FY2016

(GDUFA YEARS 2, 3, 1st QTR 4)


Significant First Generic Approvals for 2015

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Brand (Generic name) Indications (Abbreviated) Abilify® (aripiprazole) Schizophrenia, Bipolar Disorder Copaxone ® (glatiramer) Multiple sclerosis Enablex® (darifenacin) Overactive bladder Fusilev® (levoleucovorin) Supports cancer treatment Lotronex® (alosetron) Irritable bowel syndrome Integrelin® (eptifibatide) Heart attack Norvir ® (ritonavir) HIV-1 infection Orap ® (pimozide) Tourette’s Disorder Transderm Scop® (scopolamine) Motion sickness Tygacil® (tigecycline) Pneumonia, serious infections Vagifem® (estradiol) Menopause Xenazine® (tetrabenazine) Huntington’s Disease Zyvox® (linezolid) Pneumonia, serious infections

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GDUFA BACKLOG: 2866 original ANDAs 1873 PAS supplements GDUFA GOAL: 90% get first ACTION by end of GDUFA YR 5

(9/30/2017)

GDUFA Backlog Applications with First Action through 12/31/15

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Prior Approval Supplements (PAS) Exceeding GDUFA Review Goals*


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Eliminating ANDA Filing Backlog

FILING REVIEW • There is NO filing backlog

– Pre-year 3 applications: Done! – Reviewed, filed, or RTRed – FY 2015 >1,500 filing reviews completed

• Filing being done in real time

– Current: 31 days

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• First step in REVIEW • Acceptable for FILING means that

the application is sufficiently complete to permit substantive review

• It does not mean that application will be approved

• 1st inning home run vs. winning the ball game

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FILING

PRODUCTIVITY COMMUNICATION WITH INDUSTRY

EASILY CORRECTABLE DEFICIENCIES (ECDs) & INFORMATION REQUESTS (IRs)

ECD/IR

OVER 4,700 communications to

industry last FY during ANDA review


PRODUCTIVITY ANDA Complete Response (CRs)

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Exceeding Controlled Correspondence Goals

** Numbers are based on current data and will be further scrubbed for formal reporting purposes.

34 ** Numbers are based on current data and will be further scrubbed for formal reporting purposes.

Eliminated Controlled Correspondence Backlog

41 56 69

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78

154

0

50

100

150

200

250

FY 13 FY 14 FY 15

New Guidance

Revised Guidance

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134

223

Product-Specific ANDA Guidances

Notable FY2015 Product Specific Guidances

• Recommendations on more complex dosage forms – 2 inhalation powders, 3 MDI, 4 nasal sprays – 1 buccal tablet, 1 sublingual spray, 1 dental powder, 1

buccal film – 8 ophthalmic solutions or suspensions – 9 topical semi-solids, 3 topical spray/foam – 3 transdermal systems, 1 otic suspension, 2 ER

injections

• Conjugated Estrogen • Complex mixture with no previous ANDA pathway • FDA lab work on analytical methods • Significant work across CDER • http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm

428204.pdf

• Size & Shape Guidance (OGD + OPQ) – Draft published 6/18/2015 – This guidance is not being used for Filing decisions – Useful for industry to understand what FDA is looking for/at during

scientific and clinical review – http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-

gen/documents/document/ucm377938.pdf 37

Notable FY2015 Guidances (cont)

Orange Book Express Mobile App

• Search the public Orange Book Database for Approved Drugs and Patent and Exclusivity Information

• Search all marketing statuses (Rx, OTC, Discontinued) with one search

• Identify Reference Listed Drugs (RLDs) and determine if a drug product is considered to be a therapeutic equivalent

• Browse Patent Delistings and Newly Added Patents

• Launched 11/9/2015, 18K+ downloads • Available for Android and iOS devices

OUTLINE

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METRICS for Application Quality

1. RTR 2. 1st cycle approval 3. Number of review cycles

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FILING – Refuse to Receive (RTR) (Based on cohort year of submission)

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YEAR # RTR’s % of Cohort

FY2010 146 18%

FY2011 142 16%

FY2012 156 14%

FY2013 193 19%

FY2014 191 13%

FY2015 124 23%


Compared with first years of PDUFA: 10-30% Refuse to File (RTF)

16%

18%

YEAR 3 Applications • Submitted October 2014 • GDUFA GOAL DATES – January 2016

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Active Ingredient

ANDA Number Company Date of Approval

Tretinoin 207955 Spear 08/13/2015

Loperamide* 206548 Aurobindo 12/15/2015

Gabapentin 206402 Alkem 12/23/2015

Active Ingredient

ANDA Number Company Date of Tentative Approval

Diclofenac 208068 Paddock 10/14/2015

Diclofenac 208098 Taro 01/14/2016

Sildenafil* 206401 Ajanta 01/21/2016

Lurasidone 208037 MSN Labs 01/25/2016

Lurasidone 208031 Lupin 01/25/2016

Lurasidone 208066 Sun Pharma 01/25/2016

Risedronate 205280 Orchid 01/29/2016

AP or TA issued on or before GDUFA goal date *Not a first cycle AP/TA Information available at: Drugs@FDA website:

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Year 3 APPROVALS/TA Through 1/31/16 (15 month goal)

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Approved, 2

Complete Response, 38

Pending, 3

Refuse-to-Receive, 4

Tentative Approval, 4

Approved

Complete Response

Pending

Refuse-to-Receive

Tentative Approval

12% first cycle approval rate 75% complete response (will need another review cycle)

>90% met GDUFA goals


Oct 2014 Submission Status (51 Submissions) As of 1/31/16, GDUFA GOAL DATE in January 2016*

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CMC Review Cycles for ANDAs to Approval

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First Cycle Approval Rate Under PDUFA

OUTLINE

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48 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm484609.htm *Numbers are based on current data and will be further scrubbed for formal reporting purposes

GENERIC DRUG REVIEW DASHBOARD Pre-Year 3 ANDAs

(LAUNCHED 2/5/16)

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm484609.htm

ALL ANDA “active” WORKLOAD (n=6218; FDA Testimony to Senate HELP Committee, 1/28/16)

49 Includes Pre-GDUFA (“backlog”) & GDUFA ANDAs accepted for filing only; approximate workload. *Numbers are based on current data and will be further scrubbed for formal reporting purposes

COMMUNICATIONS ENHANCEMENTS FOR PRE-YEAR 3 ANDAs

• Complete Responses pending inspections

• Information Requests (IRs), Easily Correctible Deficiencies (ECDs) and Real Time Communication

• Target Action Dates (TADs) assigned & communicated to industry

– TLC for 1st generics to align with patent or exclusivity expiration

• Other launch planning communications related to TADs

• Updated Communications with Industry MAPP to formalize and clarify these changes for pre-Year 3 applications

– http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciesprocedures/ucm369599.pdf

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http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciesprocedures/ucm369599.pdf

http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciesprocedures/ucm369599.pdf

PREDICTABILITY for INDUSTRY TADs for Additional Cycles (Pre-Year 3)

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OUTLINE

1. GDUFA update 2. Output & Productivity 3. Quality of ANDA Submissions 4. Update on Pre-Year 3 cohort 5. Opportunities for Improvement &

Challenges Common Problems seen in ANDAs Ways for Industry to “Control your Destiny”

“How an ANDA Gets Approved”

Presentation at GPhA Fall Tech November 3, 2015

Speakers: Kevin Denny, (OGD) Craig Kiester (OPQ)

Presentation: 1.5 hours long, 109 slides

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• Use the right form • Complete the form entirely • If foreign, must use a US agent • Pay appropriate fees

• Point of Contact: one person vs. general

company email and phone number (e.g., [email protected])

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OPPORTUNITIES & CHALLENGES

mailto:[email protected]

• Use Cover Letter with every submission – Identify content of submission

• IR response • BE studies • New facilities

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IR responses: – Please respond to ONLY those issues raised

by FDA in IR – Please do not include:

• Lots of extraneous information over what was requested

• Tons of data, 1,000s of pages of reports • Information that is off topic • Other discipline • New facility 56

Facilities: • Need to use 356h form • New facilities in submission without flagging

this to Agency • Facilities added in IR response – out of scope • New facilities added at end of review cycle

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• Need for litigation updates as you are nearing GDUFA goal date or TAD

• Failure to provide Patent updates

• Submit these to ANDA – not to me or the RPM

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• Stay on top of: – RLD labeling changes – REMS modifications

• IF there are changes to either of these,

ANDA applicant needs to submit revised labeling or REMS

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CONCLUSIONS

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YEAR 3 METRIC GOALS How are we doing?

• GDUFA Backlog – FDA is way ahead of schedule – 86+% have received 1st action

• PASs – FDA is exceeding goals • Controls – FDA is exceeding goals

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YEAR 3 METRIC GOALS How are we doing?

• ANDAs – too soon to tell; we are confident • Amendments – too soon to tell; we are

confident

• Quality of Submissions – too soon to tell

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WHAT IS NEXT? Years 4 & 5: • Review metrics tighten • There will be up months and down months,

but overall productivity on pre-Year 3 submissions will continue to increase

Strong focus on: • TADs and related communications • First generics: Avoid FTF PIV forfeitures,

pursue timely first generic approvals 63

WORKING TOGETHER • FDA and Industry continue to work together to

ensure ultimate aims of GDUFA --- Safety, Access and Transparency -- are achieved

• Success of program is the direct result of intensive Agency-Industry collaboration

• We appreciate the open and honest dialogue to evaluate challenges and develop impactful improvements

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REAPING THE BENEFITS • FDA is fulfilling its GDUFA

commitments • In many cases, we are going above

and beyond our negotiated commitments

• We are building a robust, modern generic drug regulatory program – Sustainable and predictable – Clear and consistent communication – Fairness across applications and

applicants

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GDUFA…. Not only “Can” we do it…..we ARE DOING IT

FDA and Industry are working together to provide affordable, high quality generic medications for the

American public

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THANK YOU!

Documents

Office of Generic Drugs (OGD) Director’s Update · PDF fileOffice of Generic Drugs (OGD) Director’s Update ... February 23, 2016 . 2 Disclaimer • This presentation reflects